Preparation method of high-purity clofazimine

Abstract

The invention discloses a preparation method of high-purity clofazimine, and belongs to the technical field of drug synthesis, the key points of the technical scheme are as follows: S1, parachloroaniline, 2-fluoronitrobenzene and triethylamine are mixed and then react at 120-130 DEG C for 4.5-5.5 h, cooling is performed, absolute ethyl alcohol is added, and cooling is performed to room temperature to obtain 2-nitro-4 '-chlorodiphenylamine; s2, reducing nitryl of the 2-nitro-4 '-chlorodiphenylamine into amino, so as to obtain 2-amino-4'-chlorodiphenylamine; s3, reacting the 2-amino-4 '-chlorodiphenylamine under the action of ferric trichloride, absolute ethyl alcohol and hydrochloric acid for 9-10 hours to obtain iminophenazine hydrochloride; s4, carrying out an addition-elimination reaction on the 2-parachloroanilino-5-parachlorophenyl-3, 5-dihydro-3-iminophenazine hydrochloride, so as to obtain a clofazimine crude product; s5, refining the clofazimine crude product to obtain the high-purity clofazimine, the purity of the clofazimine reaches 99% or above by adjusting reaction parameters in each step, the clofazimine can be basically dissolved in gastric juice 60 minutes later, and the absorption efficiency is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, in particular to a method for preparing high-purity clofazimine. Background Art

[0002] Clofazimine, chemically known as 10-(p-chlorophenyl)-2,10-dihydro-3-(p-chlorophenylamino)-2-isopropyliminophenazine, exhibits strong antibacterial activity in macrophages, lacks cross-resistance with existing anti-TB drugs, is less susceptible to resistance, and exhibits synergistic effects when used in combination. Clofazimine is also highly lipid-soluble and widely distributed in human tissues. Taking it with food enhances its absorption, has a long half-life, and exhibits a post-antibiotic effect, which can shorten treatment courses and reduce relapse rates.

[0003] The existing preparation of clofazimine includes the following steps: S1, subjecting o-fluoronitrobenzene and p-chloroaniline to a nucleophilic reaction to obtain an intermediate A; S2, reducing the nitro group of intermediate A to an amino group to obtain intermediate B; S3, subjecting intermediate B to a dehydrogenation cyclization in the presence of ferric chloride, water, and hydrochloric acid to obtain a phenazine compound intermediate C; S4, subjecting intermediate C to an addition elimination reaction, and drying to obtain a crude clofazimine product; S5, refluxing and refining the crude clofazimine product and anhydrous ethanol in a certain proportion to obtain a brown-red to reddish-brown crystalline powder.

[0004] However, the clofazimine obtained by the existing preparation method of clofazimine has low purity and takes a long time to dissolve and be absorbed in gastric juice. Summary of the Invention

[0005] In order to solve the problems in the prior art, the present invention provides a method for preparing high-purity clofazimine. The present application effectively improves the purity of clofazimine by adjusting the reaction parameters in each step, so that the purity of clofazimine reaches more than 99%, thereby allowing clofazimine to be basically dissolved in gastric juice within 60 minutes, thereby improving absorption efficiency.

[0006] The present invention provides a method for preparing high-purity clofazimine using the following technical solution: A method for preparing high-purity clofazimine comprises the following steps: S1. p-Chloroaniline, 2-fluoronitrobenzene and triethylamine were mixed and stirred at 120-130° C. for 4.5-5.5 hours, then the temperature was lowered, anhydrous ethanol was added and the temperature was cooled to room temperature to obtain 2-nitro-4'-chlorodiphenylamine; S2, reducing the nitro group of 2-nitro-4'-chlorodiphenylamine to an amino group to obtain 2-amino-4'-chlorodiphenylamine; S3, reacting 2-amino-4'-chlorodiphenylamine with ferric chloride, anhydrous ethanol, and hydrochloric acid for 9-10 hours to obtain 2-p-chloroanilino-5-p-chlorophenyl-3,5-dihydro-3-iminophenazine hydrochloride; S4, subjecting 2-p-chloroanilino-5-p-chlorophenyl-3,5-dihydro-3-iminophenazine hydrochloride to an addition-elimination reaction to obtain a crude product of clofazimine; S5. Refining the crude clofazimine to obtain high-purity clofazimine.

[0007] Preferably, in step S1, when the temperature drops to 55-65° C., anhydrous ethanol is added under vacuum.

[0008] Preferably, the temperature for reducing the nitro group to the amino group in step S2 is 60-80°C.

[0009] Preferably, the reaction temperature of step S3 is 25-30°C.

[0010] Preferably, the addition-elimination reaction in step S4 is carried out at a temperature of 100-110° C. for 14.5-15.5 hours.

[0011] Preferably, in step S4, vacuum is evacuated before heating and then nitrogen is introduced to normal pressure, and the operation is repeated three times.

[0012] Preferably, the refining process in step S5 is to mix the crude clofazimine, anhydrous ethanol and medicinal charcoal, heat to 85-90° C., stir and reflux for 25-30 minutes, then pass through activated carbon, filter, cool the filtrate and centrifuge to obtain high-purity clofazimine.

[0013] Preferably, the purity of the high-purity clofazimine is greater than 99%.

[0014] In summary, the present invention has the following beneficial effects: When 2-fluoronitrobenzene is selected as the raw material in this application, it has a higher reactivity than 2-chloronitrobenzene, so that a rapid reaction can be carried out at low temperature, shortening the reaction cycle and reducing production costs. At the same time, the reaction process will be safer at a low reaction temperature. In addition, when the reactants in step S1 are reduced to 55-65 ° C and then vacuumed and anhydrous ethanol is added, the product can be precipitated synchronously with cooling, similar to recrystallization, with excellent impurity removal effect. In the addition-elimination reaction process of step S4, vacuum is first drawn before the reaction and then nitrogen is passed to normal pressure. The operation is repeated three times. When the reaction is carried out at a lower temperature, oxidation of the reactants can be effectively prevented, thereby ensuring that the impurity compound requirements in the finally generated clofazimine are met. If the reaction temperature is too high, the risk factor is large.

[0015] Therefore, the present application effectively improves the purity of clofazimine by adjusting the reaction parameters in each step, so that the purity of clofazimine reaches more than 99%, so that clofazimine can be basically dissolved in gastric juice within 60 minutes, thereby improving the absorption efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 This is the infrared spectrum of clofazimine obtained in Example 1 of the present application.

[0017] Figure 2 This is the UV-visible spectrophotometric detection spectrum of Example 1 of the present application.

[0018] Figure 3 This is the thin layer chromatogram of Example 1 of the present application. DETAILED DESCRIPTION

[0019] The present invention will be described in further detail below with reference to the accompanying drawings. All reagents without manufacturer indication are conventional reagent products that can be obtained commercially.

[0020] Example 1 A method for preparing high-purity clofazimine comprises the following steps: S1. Add p-chloroaniline to a reactor, seal it with a lid, and then evacuate it. Pipette 2-fluoronitrobenzene and triethylamine into the reactor from the feed port. After nitrogen is filled until the pressure in the reactor is zero, raise the temperature in the reactor to 120°C and stir to react for 4.5 hours. Start stirring and cool it to 5°C. Vacuum it, pump anhydrous ethanol into the liquid feed port, and then cool it to room temperature for discharge. Then, filter the reaction liquid, wash it with anhydrous ethanol, and then wash it with purified water until it is neutral, and then dry it to obtain 2-nitro-4'-chlorodiphenylamine. The yield is 92.1%, wherein the weight ratio of 2-fluoronitrobenzene: p-chloroaniline: triethylamine: anhydrous ethanol is 1:1.5:1:1; S2. 2-nitro-4'-chlorodiphenylamine and anhydrous ethanol were added to a reactor and stirred for 30 min. Purified water was then added. When the reaction solution was heated to 60° C., a 30 wt% sodium hydroxide solution was added dropwise. When the pH reached 9, thiourea dioxide was added. During the addition, the temperature of the reaction solution was controlled not to exceed 80° C. When the reaction solution became off-white, the temperature was lowered, centrifuged, washed with water until neutral, and then dried to obtain 2-amino-4'-chlorodiphenylamine. The yield was 96.0%, and the weight ratio of 2-nitro-4'-chlorodiphenylamine: anhydrous ethanol: thiourea dioxide was 1:3.2:2.3. S3. Add 2-amino-4'-chlorodiphenylamine, anhydrous ethanol, and 10 wt% hydrochloric acid to a reactor, mix and stir, add ferric chloride solution dropwise for 1 hour, react at 25°C for 9 hours after the addition, centrifuge, wash with water until neutral, and dry to obtain 2-p-chloroanilino-5-p-chlorophenyl-3,5-dihydro-3-iminophenazine hydrochloride with a yield of 98.3%, wherein the weight ratio of 2-amino-4'-chlorodiphenylamine: anhydrous ethanol: hydrochloric acid: ferric chloride solution is 1:5.4:0.4:3.3; S4. Add 2-(4-chloroanilino)-5-(4-chlorophenyl)-3,5-dihydro-3-iminophenazine hydrochloride and anhydrous ethanol to a reactor, evacuate the reactor and then introduce nitrogen to normal pressure, repeat the operation three times, then quickly draw in isopropylamine and seal the reactor, start stirring, then increase the temperature to control the reaction temperature at 100° C. and keep stirring for 14.5 hours, condense and recover the isopropylamine, wash the discharged material with anhydrous ethanol until neutral, and dry to obtain crude clofazimine with a yield of 98.2%, wherein the weight ratio of 2-(4-chloroanilino)-5-(4-chlorophenyl)-3,5-dihydro-3-iminophenazine hydrochloride: anhydrous ethanol: isopropylamine is 1:5.3:2.2; S5. Add crude clofazimine, anhydrous ethanol, and medicinal charcoal into a reactor at a weight ratio of 1:100:0.01, heat to 85°C, stir and reflux for 25 minutes, then filter the medicinal charcoal, cool the filtrate to below 10°C, and centrifuge and dry to obtain high-purity clofazimine with a yield of 90.1%. The infrared detection spectrum of the finally obtained clofazimine is as follows: Figure 1 As shown, the clofazimine crystals obtained in this example are brown-red and shiny. The reason for this is that the proportion of the main crystal form is high. When the proportion of the main crystal form is high, the solubility of clofazimine will also increase.

[0021] Example 2 A method for preparing high-purity clofazimine comprises the following steps: S1. Add p-chloroaniline to a reactor, seal it with a lid, and then evacuate it. Pipette 2-fluoronitrobenzene and triethylamine into the reactor from the feed port. After nitrogen is filled until the pressure in the reactor is zero, raise the temperature in the reactor to 125°C and stir to react for 5 hours. Then, start stirring and cool it to 60°C, evacuate it, and pump anhydrous ethanol into the liquid feed port. Then, cool it to room temperature and discharge the material. Then, filter the reaction liquid, wash it with anhydrous ethanol, and then wash it with purified water until it is neutral, and then dry it to obtain 2-nitro-4'-chlorodiphenylamine. The yield is 92.6%, wherein the weight ratio of 2-fluoronitrobenzene: p-chloroaniline: triethylamine: anhydrous ethanol is 1:1.5:1:1; S2. 2-nitro-4'-chlorodiphenylamine and anhydrous ethanol were added to a reactor and stirred for 30 min. Purified water was then added. When the reaction solution was heated to 60° C., a 30 wt% sodium hydroxide solution was added dropwise. When the pH reached 9, thiourea dioxide was added. During the addition, the temperature of the reaction solution was controlled not to exceed 80° C. When the reaction solution became off-white, the temperature was lowered, centrifuged, washed with water until neutral, and then dried to obtain 2-amino-4'-chlorodiphenylamine. The yield was 96.7%, and the weight ratio of 2-nitro-4'-chlorodiphenylamine: anhydrous ethanol: thiourea dioxide was 1:3.2:2.3. S3. Add 2-amino-4'-chlorodiphenylamine, anhydrous ethanol, and 10 wt% hydrochloric acid to a reactor, mix and stir, add ferric chloride solution dropwise for 1 hour, react at 25°C for 9 hours after the addition, centrifuge, wash with water until neutral, and dry to obtain 2-p-chloroanilino-5-p-chlorophenyl-3,5-dihydro-3-iminophenazine hydrochloride with a yield of 98.4%, wherein the weight ratio of 2-amino-4'-chlorodiphenylamine: anhydrous ethanol: hydrochloric acid: ferric chloride solution is 1:5.4:0.4:3.3; S4. Add 2-(4-chloroanilino)-5-(4-chlorophenyl)-3,5-dihydro-3-iminophenazine hydrochloride and anhydrous ethanol to a reaction kettle, evacuate the reactor and then introduce nitrogen to normal pressure, repeat the operation three times, then quickly draw in isopropylamine and seal the reactor, start stirring, then increase the temperature to control the reaction temperature at 105° C. and keep stirring for 15 hours, condense and recover the isopropylamine, wash the discharged material with anhydrous ethanol until neutral, and dry to obtain crude clofazimine with a yield of 98.7%, wherein the weight ratio of 2-(4-chloroanilino)-5-(4-chlorophenyl)-3,5-dihydro-3-iminophenazine hydrochloride: anhydrous ethanol: isopropylamine is 1:5.3:2.2; S5. Add crude clofazimine, anhydrous ethanol, and medicinal charcoal into a reactor at a weight ratio of 1:100:0.01, heat to 90°C, stir and reflux for 30 minutes, then filter the medicinal charcoal, cool the filtrate to below 10°C, and centrifuge and dry to obtain high-purity clofazimine with a yield of 92.6%. The infrared detection spectrum of the finally obtained clofazimine is the same as Figure 1 The clofazimine crystals obtained in this embodiment are brown-red and shiny because the main crystal form accounts for a high proportion. When the main crystal form accounts for a high proportion, the solubility of clofazimine will also increase.

[0022] Example 3 A method for preparing high-purity clofazimine comprises the following steps: S1. Add p-chloroaniline to a reactor, seal it with a lid, and then evacuate it. Pipette 2-fluoronitrobenzene and triethylamine into the reactor from the feed port. After nitrogen is filled until the pressure of the reactor is zero, raise the temperature in the reactor to 130°C and stir to react for 5.5 hours. Then, start stirring and cool it to 65°C, evacuate it, pump anhydrous ethanol into the liquid feed port, and then cool it to room temperature for discharge. Then, filter the reaction liquid, wash it with anhydrous ethanol, and then wash it with purified water until it is neutral, and then dry it to obtain 2-nitro-4'-chlorodiphenylamine. The yield is 92.2%, wherein the weight ratio of 2-fluoronitrobenzene: p-chloroaniline: triethylamine: anhydrous ethanol is 1:1.5:1:1; S2. Add 2-nitro-4'-chlorodiphenylamine and anhydrous ethanol to a reactor and stir for 30 minutes. Then add purified water. When the reaction solution is heated to 60°C, begin to dropwise add a 30wt% sodium hydroxide solution. When the pH is 9, add thiourea dioxide. During the addition, control the temperature of the reaction solution not to exceed 80°C. When the reaction solution becomes off-white, cool it, centrifuge it, wash it with water until it is neutral, and then dry it to obtain 2-amino-4'-chlorodiphenylamine. The yield is 96.1%, wherein the weight ratio of 2-nitro-4'-chlorodiphenylamine: anhydrous ethanol: thiourea dioxide is 1:3.2:2.3; S3. Add 2-amino-4'-chlorodiphenylamine, anhydrous ethanol, and 10 wt% hydrochloric acid to a reactor, mix and stir, add ferric chloride solution dropwise for 1 hour, react at 25°C for 10 hours after the addition, centrifuge, wash with water until neutral, and dry to obtain 2-p-chloroanilino-5-p-chlorophenyl-3,5-dihydro-3-iminophenazine hydrochloride with a yield of 98.3%, wherein the weight ratio of 2-amino-4'-chlorodiphenylamine: anhydrous ethanol: hydrochloric acid: ferric chloride solution is 1:5.4:0.4:3.3; S4. Add 2-(4-chloroanilino)-5-(4-chlorophenyl)-3,5-dihydro-3-iminophenazine hydrochloride and anhydrous ethanol to a reaction kettle, evacuate the reactor and then introduce nitrogen to normal pressure, repeat the operation three times, then quickly draw in isopropylamine and seal the reactor, start stirring, then increase the temperature to control the reaction temperature at 110° C. and keep stirring for 15.5 hours, condense and recover the isopropylamine, wash the discharged material with anhydrous ethanol until neutral, and dry to obtain crude clofazimine with a yield of 98.5%, wherein the weight ratio of 2-(4-chloroanilino)-5-(4-chlorophenyl)-3,5-dihydro-3-iminophenazine hydrochloride: anhydrous ethanol: isopropylamine is 1:5.3:2.2; S5. Add crude clofazimine, anhydrous ethanol, and medicinal charcoal into a reactor at a weight ratio of 1:100:0.01, heat to 90°C, stir and reflux for 30 minutes, then filter the medicinal charcoal, cool the filtrate to below 10°C, and centrifuge and dry to obtain high-purity clofazimine with a yield of 91.6%. The infrared detection spectrum of the finally obtained clofazimine is the same as Figure 1The clofazimine crystals obtained in this embodiment are brown-red and shiny because the main crystal form accounts for a high proportion. When the main crystal form accounts for a high proportion, the solubility of clofazimine will also increase.

[0023] Control Example The preparation process of Example 14 in the preparation method of chlorphenazine in Chinese patent CN117343021A was adopted.

[0024] Comparative Example 1 A method for preparing clofazimine, which differs from Example 1 in that step S4 does not include the step of evacuating the solution and then passing nitrogen to normal pressure, and the remaining steps are the same as those in Example 1. The yield of the crude clofazimine obtained in step S4 is 93.6%, and the yield of the clofazimine finally obtained in step S5 is 86.3%. The clofazimine crystals are dark brown-red, which is caused by a low proportion of the main crystal form.

[0025] Performance testing 1. The high-purity clofazimine soft capsules obtained in the above examples, control examples and comparative examples were subjected to a dissolution test. The specific steps are as follows: 1.1 Dissolution determination method Tested according to the dissolution and dilution method (tested in accordance with the relevant provisions of the second method of Part 0931 of the General Rules of the Fourth Part of the 2020 Chinese Pharmacopoeia) Dissolution medium: 50% n-propanol + artificial gastric juice + 1.5wt% SDS, 900mL; Dissolution method: dissolution speed is 100 rpm; Detection method: High performance liquid chromatography was used, and the chromatographic column was Ultimate XB-C8 4.6mm×250mm, 5μm; Mobile phase: phosphate buffer (2.475 g of sodium dodecyl sulfate, 0.935 g of tetrabutylammonium hydrogen sulfate, and 0.885 g of disodium hydrogen phosphate dodecahydrate, dissolved in 500 mL of water, and adjusted to pH 3.0 with phosphoric acid) and acetonitrile in a volume ratio of 35:45. Elution was isocratic. The flow rate was 1.5 mL / min, the detection wavelength was 280 nm, the column temperature was 30 °C, and the injection volume was 10 μL; The test run time is 13 minutes.

[0026] 1.2 Preparation of clofazimine soft capsules The clofazimine raw material obtained in the above example was prepared into clofazimine soft capsules as follows: 1.2.1 Preparation of glue solution: Mix the prescribed amount of red iron oxide, black iron oxide and glycerol in a weight ratio of 32:5:1, add them gradually into a grinder and grind for 10 minutes. After passing through a 100-mesh sieve, it is used as a coloring suspension. Purified water, glycerol, and ethylparaben ethanol solution in a weight ratio of 3:1:1 are added to a glue tank in sequence. Stir until the temperature reaches 55-60°C, then add gelatin. After the gelatin is dissolved, add the reserved colorant suspension. Stir for 30 minutes, then stop stirring, eliminate bubbles, and control the viscosity to be in the range of 10,000-20,000 mPa·s.

[0027] 1.2.2 Preparation of drug solution: Mix the prescribed amount of clofazimine, vegetable oil, propylene glycol and BHT in a weight ratio of 100:225:8:0.2, add them gradually into the grinder, circulate and grind for 15-20 minutes, and pass through a 100-mesh sieve.

[0028] 1.2.3 Pill pressing: Pour the prepared liquid medicine into the medicine supply system of the pressing equipment, spray it between the two adjusted films through the nozzle, and press it into pills through the mold.

[0029] The capsules obtained above were added to the dissolution medium, and samples were taken for testing at 5 min, 10 min, 15 min, 30 min, 60 min, 90 min, and 120 min, respectively.

[0030] The dissolution test results are shown in the table below: almost all dissolved within 60 minutes.

[0031] It can be seen from the test results in the above table that the cumulative solubility of clofazimine obtained in the examples of the present application at 60 minutes can reach a minimum of 98.9%, which is equivalent to almost complete dissolution. The cumulative dissolution of clofazimine capsules obtained by the preparation method of the comparative example at 60 minutes is 78.7%, and its solubility at 120 minutes is 97.3%, which is the state of almost complete dissolution. Therefore, it can be seen from the recovery rates of the control examples and the examples that the recovery rates of the present application are all above 90%, while the recovery rate of the control example is 80.43%, which is much lower than the recovery rate in the present application. This shows that the present application effectively improves the recovery rate of the final product by adjusting the reaction temperature and the raw materials of the reaction, thereby improving the utilization efficiency of the raw materials.

[0032] Compared with Example 1, in Comparative Example 1, the clofazimine capsules were almost completely dissolved after 90 minutes, indicating that vacuuming and nitrogen-gasing to normal pressure in step S4 can reduce the impurity content in the crude clofazimine product.

[0033] 2. Content detection of the high-purity clofazimine obtained in the above example 2.1 The content of clofazimine was determined according to the 2020 edition of the Chinese Pharmacopoeia, Part II. Specifically, about 0.3 g of clofazimine obtained in the embodiment of the present application was taken, accurately weighed, dissolved in 25 mL of glacial acetic acid, and titrated with perchloric acid titrant (0.1 mol / L) according to the potentiometric titration method. The titration result was corrected by a blank test (ie, no clofazimine was added and blank subtraction was performed). Each 1 mL of perchloric acid titrant (0.1 mol / L) was equivalent to 47.34 mg of C 27 H 22 C l2 N4. The test results are shown in the following table project purity% Example 1 99.5 Example 2 99.6 Example 3 99.5 Control Example 92.7 Comparative Example 1 96.5 As can be seen from the above table: the purity of clofazimine obtained by the preparation method of the present application reached more than 99%, while the purity of clofazimine obtained in the control example was 92.7%. Combined with the cumulative dissolution test results, it can be seen that due to the improvement in the purity of clofazimine, the solubility of clofazimine capsules in gastric juice is significantly shortened, thereby facilitating faster absorption by the human body and faster drug effect. In addition, after adjusting various preparation process parameters, the purity of clofazimine in the present application has been significantly improved compared with the purity of clofazimine obtained by the existing preparation process, indicating that the adjustment of the process parameters of the present application effectively controls the formation of impurities in clofazimine.

[0034] Compared with Example 1, Comparative Example 1 omitted the step of evacuating the mixture to atmospheric pressure with nitrogen, which significantly reduced the purity of the final product, clofazimine. It can be seen that the combination of the steps in this application can effectively ensure that the purity of the final product reaches 99%.

[0035] 2.2 The clofazimine obtained in Example 1 was identified as follows The identification method is as follows: take about 15 mg of clofazimine obtained in the above example and place it in a 100 mL volumetric flask, add chloroform to dissolve and dilute to the scale, shake well, take 5 mL and place it in another 100 mL volumetric flask, add 10 mL of 0.1 mol / L hydrochloric acid methanol solution, dilute to the scale with chloroform, shake well, and measure according to the ultraviolet-visible spectrophotometry method (General Rule 0401). Maximum absorption is found at wavelengths of 289 nm and 491 nm.

[0036] The UV-visible spectrophotometric detection spectrum of clofazimine obtained in Example 1 of the present application is as follows Figure 2 As shown, it has maximum absorption at wavelengths of 289±2nm and 491±2nm, indicating that the clofazimine obtained by the preparation process of Example 1 of the present application meets the requirements of the Chinese Pharmacopoeia.

[0037] 2.3 The detection method for clofazimine-related substances is as follows Related substances are tested according to the thin layer chromatography method (General Chapter 0502).

[0038] Test solution: Take an appropriate amount of clofazimine obtained in Example 1 above, dissolve it in chloroform and dilute it to make a solution of about 20 mg per 1 mL.

[0039] Control solution (1) Accurately measure an appropriate amount of the test solution and quantitatively dilute it with chloroform to make a solution containing approximately 0.10 mg per 1 mL; Control solution (2): Accurately measure an appropriate amount of the test solution and quantitatively dilute it with chloroform to produce a solution containing approximately 0.16 mg per 1 mL.

[0040] Chromatographic conditions: Silica gel GF254 thin layer plates (the thin layer plates were pre-saturated with 3% ammonia solution for 30 minutes) were used, and dichloromethane-n-propanol (85:4) was used as the developing solvent.

[0041] Determination method: Pipette 5 μL of each of the three solutions mentioned above, spot them on the same thin layer plate, unfold, dry, unfold again, dry, examine under ultraviolet light (254 nm), and then spray with 50% sulfuric acid solution and examine again.

[0042] Limits: If impurity spots appear in the test solution, they must not be darker than the main spots of the control solution (2), and there must not be more than two spots darker than the main spots of the control solution (1).

[0043] Thin layer chromatogram Figure 3 As shown, thin layer chromatography detection determined that the clofazimine prepared by the preparation process of Example 1 of the present application meets the requirements of the Chinese Pharmacopoeia.

[0044] The embodiments of this specific implementation method are all preferred embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Therefore, any equivalent changes made based on the structure, shape, and principle of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing high-purity clofazimine, characterized in that: The steps include: S1. p-Chloroaniline, 2-fluoronitrobenzene and triethylamine were mixed and stirred at 120-130° C. for 4.5-5.5 hours, then the temperature was lowered, anhydrous ethanol was added and the temperature was cooled to room temperature to obtain 2-nitro-4'-chlorodiphenylamine; S2, reducing the nitro group of 2-nitro-4'-chlorodiphenylamine to an amino group to obtain 2-amino-4'-chlorodiphenylamine; S3, reacting 2-amino-4'-chlorodiphenylamine with ferric chloride, anhydrous ethanol, and hydrochloric acid for 9-10 hours to obtain 2-p-chloroanilino-5-p-chlorophenyl-3,5-dihydro-3-iminophenazine hydrochloride; S4, subjecting 2-p-chloroanilino-5-p-chlorophenyl-3,5-dihydro-3-iminophenazine hydrochloride to an addition-elimination reaction to obtain a crude product of clofazimine; S5. Refining the crude clofazimine to obtain high-purity clofazimine.

2. The method for preparing high-purity clofazimine according to claim 1, wherein: When the temperature drops to 55-65° C. in step S1, anhydrous ethanol is added under vacuum.

3. The method for preparing high-purity clofazimine according to claim 1, wherein: The temperature for reducing the nitro group to the amino group in step S2 is 60-80°C.

4. The method for preparing high-purity clofazimine according to claim 1, wherein: The reaction temperature of step S3 is 25-30°C.

5. The method for preparing high-purity clofazimine according to claim 1, wherein: The addition-elimination reaction in step S4 is carried out at a temperature of 100-110° C. for 14.5-15.5 hours.

6. The method for preparing high-purity clofazimine according to claim 5, wherein: In step S4, the vacuum is evacuated before heating and then nitrogen is introduced to normal pressure, and the operation is repeated three times.

7. The method for preparing high-purity clofazimine according to claim 1, wherein: The refining process in step S5 is to mix the crude clofazimine, anhydrous ethanol and medicinal charcoal, heat to 85-90° C., stir and reflux for 25-30 minutes, then pass through activated carbon, filter, cool the filtrate and centrifuge to obtain high-purity clofazimine.

8. The method for preparing high-purity clofazimine according to claim 1, wherein: The purity of the high-purity clofazimine is greater than 99%.

Images